Gut Microbes Alter Fly Walking Activity

NEWS & VIEWS RESEARCH

MICROBIOLOGY with xylose isomerase, and report that the trehalose treatment caused the flies’ walking speed to increase. The authors proceeded to investigate the Gut microbes alter fly neural basis of the hyperactivity phenomenon. They used genetic approaches to activate neurons that regulate locomotion in D. mela- walking activity nogaster and the results focused their attention on a type of neuron called an octopaminergic A gut bacterium has been found to modulate locomotor activity in the fruit fly neuron, which produces the neurotransmit- Drosophila melanogaster. This effect is mediated by the level of a sugar and the ter molecule octopamine. Schretter et al. found activity of neurons that produce the molecule octopamine. See Letter p.402 that the walking activity of flies that lacked gut bacteria but had been given xylose isomerase was increased by activation of the genes ANGELA E. DOUGLAS by L. brevis, reduces locomotor activity in encoding enzymes needed for the synthesis D. melanogaster (Fig. 1). Further experiments of octopamine. Such an effect on locomotion s the refrain that “my microbes make me do revealed that supplying xylose isomerase to was not observed for other neurotransmitters it” true? Scientific reviews and the popular flies whose bacteria had been eliminated was they tested. Furthermore, the authors observed press often report that microbes can influ- necessary and sufficient to modulate fly loco- that the flies with their natural microbiota and Ience many aspects of the behaviour of their motion. those that had been treated to remove gut bac- healthy animal or human hosts, from cogni- How does xylose isomerase cause D. mela- teria but had received xylose isomerase both tion to social interactions to emotional state1. nogaster to slow down? The enzyme mediates walked faster if they received octopamine. If this is true, perhaps future microbial-based the interconversion of certain sugar mole- Octopamine is a well-characterized regula- therapies might be used to improve men- cules — the change of glucose into fructose, for tor of locomotion in flies. In vertebrates, the tal health. Yet the evidence for most of these example. Schretter and colleagues found that neurotransmitter molecule noradrenaline, claims of microbial effects is limited. Experi- the flies treated to remove their gut bacteria which is related in structure to octopamine, ments are urgently needed that definitively have a higher level of the sugar trehalose than fulfils a similar role in promoting physical test whether bacteria can have a causal role do those that retain their usual microbiota. activity5. Work remains to be done to fill in in behaviour, and that identify the underlying Perhaps this means that xylose isomerase the gaps in explaining how xylose isomerase mechanisms. On page 402, Schretter et al.2 decreases the availability of a glucose sub- affects the level of trehalose in the fruit fly and provide a superb example of rigorous scien- strate needed for the synthesis of trehalose. the activity of octopamine-producing neurons tific analysis, in which they demonstrate that The authors administered trehalose to flies in the brain. Nevertheless, one key conclusion the walking activity of the fruit fly Drosophila that lacked gut bacteria and had been provided emerges: the effect of bacterial products on fly melanogaster can be affected by a specific gut bacterium. The authors identify a bacterial enzyme that mediates this effect, and establish a b aspects of the mechanism by which the fruit fly Walking-path responds to the bacterium. trace Schretter et al. used standard techniques to analyse the bacterial residents of the gut. The Fruit y with Fruit y lacking natural gut microbes Lactobacillus brevis authors compared walking activity in flies harbouring their natural gut microbes (the microbiota) and flies that had been treated to eliminate the gut bacteria, and they observed that the treated flies were hyperactive in com-

parison to the others. These hyperactive flies Low activity of High activity of walked faster and for longer than the others, Xylose octopaminergic octopaminergic but their daily (circadian) rhythms of activ- isomerase neuron neuron ity and sleep were not perturbed. To determine the microbes associated with this effect, Schretter et al. supplied the hyperactive flies ↓ ↑ with various bacteria, and found that the Trehalose bacterium Lactobacillus brevis restored walking activity to the level observed in flies that Lactobacillus retained their complete microbiota. brevis There is a common expectation that gut microbes influence animal behaviour by producing small metabolites, including Figure 1 | A gut bacterium affects walking activity in the fruit fly Drosophila melanogaster. Schretter neurotransmitter molecules, which interact et al.2 used imaging approaches to track fly movement and found that (a) fruit flies that have their directly with the nervous system in the gut natural gut microbes were less active than (b) flies that lack the gut bacterium Lactobacillus brevis. a, The or that enter the bloodstream and from there authors reveal that the enzyme xylose isomerase produced by L. brevis is key to this phenomenon. This reach the brain3,4. However, the bacterial prod- enzyme modifies certain sugars, which leads, by an unknown process, to a decrease in the level of the sugar trehalose in the body of flies in which this bacterial enzyme is present. The results of the authors’ uct identified by Schretter and colleagues as experiments are consistent with a model in which a decrease in trehalose is accompanied by a decrease in involved in walking behaviour does not fit this the activity of octopaminergic neurons (those that produce the neurotransmitter molecule octopamine) paradigm. The authors provide persuasive evi- that regulate fly locomotion. b, Compared with flies that have their natural gut microbes, flies lacking dence that the presence of the sugar-modifying L. brevis have higher levels of the sugar trehalose in their body and are proposed to have higher activity of enzyme xylose isomerase, which is produced octopaminergic neurons.

RESEARCH NEWS & VIEWS locomotion is mediated by the modulation L. brevis and of L. brevis mutants lacking Angela E. Douglas is in the Departments of of known circuits that control behaviour and xylose isomerase, to determine whether this Entomology and of Molecular Biology and not through previously unknown regulatory enzyme enhances the fitness of the bacterium Genetics, Cornell University, Ithaca, New York mechanisms. and whether any fitness effects depend on fly 14853, USA. Why does L. brevis make xylose isomerase? locomotor activity. e-mail: [email protected] It should not be assumed that this is a specific The most important question to ask next 1. Mohajeri, M. H., La Fata, G., Steinert, R. E. & Weber, adaptation to life in a D. melanogaster host. is whether the effect of L. brevis and xylose P. Nutr. Rev. 76, 481–496 (2018). This bacterium is not specialized to exist isomerase on the locomotor activity of D. mel- 2. Schretter, C. E. et al. Nature 563, 402–406 only in the fruit fly gut. It maintains substan- anogaster is relevant to animal behaviour in (2018). tial free-living populations6 and is neither general, including that of humans and other 3. Cryan, J. F. & Dinan, T. G. Nature Rev. Neurosci. 13, universally present nor abundant in D. mel- mammals. As with many other discoveries first 701–712 (2012). 4. Sharon, G. et al. Cell Metab. 20, 719–730 (2014). anogaster populations in the natural environ- made in D. melanogaster8, perfect correspond- 7 5. Roeder, T. Annu. Rev. Entomol. 50, 447–477 ment . Xylose isomerase probably functions ence with mammalian systems is unlikely. (2005). to increase the diversity of the carbon sources Schretter and colleagues’ study does, however, 6. Duar, R. M. et al. FEMS Microbiol. Rev. 41, S27–S48 that L. brevis can exploit, as is the case for the alert microbiologists and those studying ani- (2017). many other bacteria that produce this enzyme. mal behaviour to pay attention to the enzymes 7. Bost, A. et al. Mol. Ecol. 27, 1848–1859 (2018). 8. Letsou, A. & Bohmann, D. Dev. Dyn. 232, 526–528 It would be interesting to learn the outcome of gut bacteria and their possible effects on (2005). of experiments comparing the abundance sugar metabolism and on the neuronal circuits in D. melanogaster of resident wild-type regulating walking activity. ■ This article was published online on 24 October 2018.

METABOLISM the essential amino acid tryptophan (Trp)2. Mutations that disrupt the enzymes respon- sible for converting Trp to NAD+ result in multi-system developmental alterations in A back door to humans3, demonstrating the importance of this de novo pathway. Katsyuba et al. set out to study α-amino-β- improved health carboxymuconate-ε-semialdehyde (ACMS), an unstable and little-studied intermediate of The coenzyme NAD+ can be produced from the amino acid tryptophan. It the Trp pathway. ACMS can either spontane- emerges that inhibiting an enzyme that degrades an intermediate in this pathway ously convert to the next intermediate on the can help to combat kidney and liver diseases in mouse models. See Article p.354 path to NAD+, or can be degraded by a train of enzymes, starting with ACMS decarboxylase (ACMSD). As such, ACMSD would be pre- SAMIR M. PARIKH rodents relies on the recycling of a molecule dicted to limit the amount of NAD+ produced called nicotinamide (Nam) that is either through de novo synthesis. ACMSD is evolu- hroughout the history of life on Earth, ingested or released by enzymes that con- tionarily conserved from the nematode worm there has been a requirement for small sume NAD+ (Fig. 1). There are several other C. elegans to mice4 — an observation that is molecules called nucleotides. Long routes of NAD+ production, including a striking because, until recently, nematodes Tchains of nucleotides make up the genetic code, de novo synthesis pathway that starts with were not thought to synthesize NAD+ de novo. and single nucleotides transduce The authors inhibited the signals or transfer energy. In addi- acsd-1 gene, which encodes the tion, a dimeric form of nucleotide Salvage pathway De novo pathway equivalent of ACMSD in nema- called nicotinamide adenine dinu- todes. This inhibition did increase cleotide (NAD+) serves at least NAD+ levels. Increasing NAD+ is two pivotal cellular functions. well known to extend lifespan in The first is to shuttle high-energy Nam NAD+ ACMS Trp worms, and the authors found electrons to enzymatic complexes that lifespan was longer in the ACMSD found in organelles called mito- worms in which acsd-1 expression chondria, where their energy can was completely blocked. Moreo- NAD+ –consuming Inhibitors be efficiently harvested; the sec- enzymes Pic ver, preventing acsd-1 expres- ond is as a substrate for enzymes sion led to molecular responses such as sirtuins, which regulate Protection against that have been linked to defence 5,6 many cellular behaviours. On liver and kidney diseases against ageing : increased activa- page 354, Katsyuba et al.1 shed tion of the sirtuin enzyme sir-2.1; light on a fundamental mecha- Figure 1 | NAD+ biosynthesis in disease. When the coenzyme nicotinamide enhanced mitochondrial func- nism by which the correct levels adenine dinucleotide (NAD+) is consumed by enzymes, nicotinamide (Nam) tion; and a protective mitochon- of NAD+ are maintained in cells, is generated as a reaction product. Through a recycling mechanism called the drial stress response. salvage pathway, NAD+ can then be regenerated. Nam salvage is considered and demonstrate how augment- + + In mice and humans, ACMSD ing this pathway can affect disease. the predominant mechanism for NAD biosynthesis, but NAD can also be is most highly expressed in the generated through multiple other routes. One of these is the de novo pathway, 7 In simple terms, the available + liver and kidney , and a recent + whereby the amino acid tryptophan (Trp) is converted to NAD through pool of NAD in a cell is gov- several intermediates, including α-amino-β-carboxymuconate-ε-semialdehyde study indicates that these are the erned by the balance between main organs for Trp-dependent (ACMS). This pathway can be depleted by the enzyme ACMS decarboxylase + 8 its generation and its consump- (ACMSD), which degrades ACMS to picolinic acid (Pic). Katsyuba et al.1 report NAD generation . Katsyuba tion. The predominant pathway that chemical inhibition of ACMSD raises NAD+ levels in mice and nematode et al. found that inhibition of by which NAD+ is generated in worms, and improves outcomes in mouse models of liver and kidney diseases. the Acmsd gene increased NAD+