Elsevier

Current Opinion in Immunology

Volume 30, October 2014, Pages 48-53
Current Opinion in Immunology

Homeostasis between gut-associated microorganisms and the immune system in Drosophila

https://doi.org/10.1016/j.coi.2014.06.006Get rights and content

Highlights

  • Uracil is a metabolic signature of noncommensal bacteria in Drosophila gut epithelia.

  • The Drosophila gut mounts innate immune response by sensing bacterial uracil.

  • Uracil release is absent or reduced in major commensal bacteria.

  • Bacterial-derived uracil acts as a pro-oxidant in gut epithelia.

The metabolic activities of a given gut bacterium or gut commensal community fluctuate in a manner largely depending on the physicochemical parameters within the gut niche. Recognition of the bacterial metabolic status in situ, by a sensing of the gut metabolites as a signature of a specific bacterial metabolic activity, has been suggested to be a highly beneficial means for the host to maintain gut–microbe homeostasis. Recently, analysis of Drosophila gut immunity revealed that bacterial-derived uracil and uracil-modulated intestinal reactive oxygen species (ROS) generation play a pivotal role in diverse aspects of host–microbe interactions, such as pathogen clearance, commensal protection, intestinal cell regeneration, colitogenesis, and possibly also interorgan immunological communication. A deeper understanding of the role of uracil in Drosophila immunity will provide additional insight into the molecular mechanisms underlying host–microbe symbiosis and dysbiosis.

Introduction

The metazoan intestine is home to numerous microorganisms [1, 2, 3]. The evolutionarily ancient relationship between the gut and microbiota is considered to be essentially symbiotic and/or commensal [4, 5]. However, in some cases, the relationship becomes deleterious, which may affect host fitness and result in disease [1]. Therefore, understanding the molecular mechanisms underlying the gut–microbiota relationship is of central importance to host physiology. Among different environmental factors affecting gut physiology, the gut microbiotas are unique in that they are metabolically active ‘biotic’ environmental factors containing their respective genomes, the so-called environmental genomes or metagenomes. It is evident that gut microbiomes produce many different metabolites comprised of small organic molecules that stimulate host cells [6, 7]. It has been shown that ∼10% of the most commonly observed metabolites differ significantly in concentration between germ-free and conventional animals harboring natural gut microbiota [8]. It should be noted that bacterial metabolic activity and the metabolites are not constant, but rather, are highly variable depending on the various physicochemical parameters of the specific gut environment [6, 7]. Accumulating evidence has shown that bacterial metabolites are deeply involved in the regulation of the host immune system, both locally at the gut cell level and systemically at the whole body level [4]. However, the mechanisms underlying gut metabolite-modulated host immune regulation are still obscure. In this minireview, we will discuss the role of the bacterial metabolite uracil on host immunity and host–microbe homeostasis in Drosophila.

Section snippets

Pattern recognition mechanism and innate immunity in the Drosophila gut

How do host cells recognize bacterial cells? At present, one of the best-known mechanisms for the bacterial recognition is the pattern recognition mechanism, that is, the recognition of microbe-derived molecular patterns [that are commonly found in most bacteria, such as lipopolysaccharide (LPS) and peptidoglycan (PG), that are absent from host cells] via host pattern recognition receptors (PRRs) [9]. The utilization of Drosophila in the study of host–microbe interactions has proven to be

Is uracil a specific metabolic signature of noncommensal bacteria?

Are gut epithelia able to distinguish between beneficial commensal bacteria from noncommensal bacteria, including pathogens? This is one of most fundamental questions that can be asked with regard to all metazoans harboring a microbial realm in their gut. Considering that both noncommensal bacteria and commensal bacteria contain PG as a common ligand and thus are recognized by PGRP-LE/LC (Figure 1), it is unclear how gut epithelia mount an immune response against noncommensal bacteria while

How is it that uracil release is absent or reduced in commensal bacteria?

In the Drosophila gut, it has been demonstrated that the major commensal bacteria do not release uracil (or do release less amounts of uracil), whereas some of the minor commensal bacteria do (e.g. Gluconobacter mobifer and Lactobacillus brevis) [32••]. Constitutive uracil release from these minor commensal bacteria is found to be colitogenic to host cells by inducing chronic DUOX activation. Introducing a mutation into the UMP/uracil biosynthesis pathway in these colitogenic bacteria is

Does the uracil-induced ROS molecule act as a second messenger controlling gut tissue homeostasis and interorgan communication?

It has been shown that pathogen infection not only provokes gut inflammation but also severely damages gut barrier epithelial cells in a way that may affect tissue integrity [39]. Damaged enterocytes are rapidly replenished by accelerating the epithelial cell renewal program. This program, including intestinal stem cell (ISC) proliferation and differentiation into enterblasts and then into mature enterocytes [39], which is essential for host survival to gut infection, has been extensively

Future directions

Maintaining a healthy gut–microbe interaction is a delicate task for the metazoans, due to the pro-inflammatory characteristics of bacteria. Not surprisingly, many inflammatory diseases frequently occur at the epithelial barrier due to the gut–microbe imbalance [45]. Although recent reports have clearly suggested that the uracil-modulated DUOX-ROS system in the gut epithelia play a central role in gut–microbe symbiosis/dysbiosis in Drosophila [32••], many important questions have yet to be

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The author apologizes to colleagues whose work could not be directly cited due to space restrictions. This study was supported by the National Creative Research Initiative Program (No. 20120000231) from National Research Foundation of South Korea and Samsung Science & Technology Foundation (No. SSTF-BA1401-15).

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