The Acetate Switch of an Intestinal Pathogen Disrupts Host Insulin Signaling and Lipid Metabolism

Hang, Saiyu; Purdy, Alexandra E.; Robins, William; Wang, Zhipeng; Mandal, Manabendra; Chang, Sarah; Mekalanos, John J.; Watnick, Paula I.

doi:10.1016/j.chom.2014.10.006

Cited by 94 publications

(144 citation statements)

References 44 publications

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“…Of the 11 modules identified, four modules (comprising 61% of genes in the network) showed no significant structural alterations between gnotobiotic and axenic flies, but the seven modules that did exhibit microbiota-dependent structure are dominated by genes with metabolic and immunological functions. These results are congruent with published evidence for microbial effects on vitamin, sugar and amino acid nutrition [13, 24, 26–28], as well as immune responses, digestion and gut cell division [13, 17, 29–31]. Altered coexpression of metabolic and signaling regulators may account for data showing that the effects of dietary change on nutrient stores are exaggerated in axenic flies, relative to flies with an unmanipulated microbiota [13].…”

Section: Discussionsupporting

confidence: 87%

The Drosophila transcriptional network is structured by microbiota

2016

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BackgroundResident microorganisms (microbiota) have far-reaching effects on the biology of their animal hosts, with major consequences for the host’s health and fitness. A full understanding of microbiota-dependent gene regulation requires analysis of the overall architecture of the host transcriptome, by identifying suites of genes that are expressed synchronously. In this study, we investigated the impact of the microbiota on gene coexpression in Drosophila.ResultsOur transcriptomic analysis, of 17 lines representative of the global genetic diversity of Drosophila, yielded a total of 11 transcriptional modules of co-expressed genes. For seven of these modules, the strength of the transcriptional network (defined as gene-gene coexpression) differed significantly between flies bearing a defined gut microbiota (gnotobiotic flies) and flies reared under microbiologically sterile conditions (axenic flies). Furthermore, gene coexpression was uniformly stronger in these microbiota-dependent modules than in both the microbiota-independent modules in gnotobiotic flies and all modules in axenic flies, indicating that the presence of the microbiota directs gene regulation in a subset of the transcriptome. The genes constituting the microbiota-dependent transcriptional modules include regulators of growth, metabolism and neurophysiology, previously implicated in mediating phenotypic effects of microbiota on Drosophila phenotype. Together these results provide the first evidence that the microbiota enhances the coexpression of specific and functionally-related genes relative to the animal’s intrinsic baseline level of coexpression.ConclusionsOur system-wide analysis demonstrates that the presence of microbiota enhances gene coexpression, thereby structuring the transcriptional network in the animal host. This finding has potentially major implications for understanding of the mechanisms by which microbiota affect host health and fitness, and the ways in which hosts and their resident microbiota coevolve.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3307-9) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 87%

The Drosophila transcriptional network is structured by microbiota

2016

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“…Interestingly, genes involved in xenobiotic metabolism are indirectly activated by toxic by-products of microbes and pathogens, through the cellular surveillance-activated detoxification and defense (cSADD) system (40), which senses xenobiotics through the dysfunction in cellular processes that they cause, including decreased host translation and altered metabolism (41). Importantly, microbes and pathogens can alter metabolism in the gut, resulting in lower IIS (42). Organisms may hence have evolved systems to sense lowered IIS as an indirect signal of the presence of pathogens and mount cSADD as a defense response, thus inducing a form of hormesis.…”

Section: Discussionmentioning

confidence: 99%

Nuclear hormone receptor DHR96 mediates the resistance to xenobiotics but not the increased lifespan of insulin-mutant Drosophila

Afschar

Toivonen

Hoffmann

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Lifespan of laboratory animals can be increased by genetic, pharmacological, and dietary interventions. Increased expression of genes involved in xenobiotic metabolism, together with resistance to xenobiotics, are frequent correlates of lifespan extension in the nematode worm Caenorhabditis elegans, the fruit fly Drosophila, and mice. The Green Theory of Aging suggests that this association is causal, with the ability of cells to rid themselves of lipophilic toxins limiting normal lifespan. To test this idea, we experimentally increased resistance of Drosophila to the xenobiotic dichlordiphenyltrichlorethan (DDT), by artificial selection or by transgenic expression of a gene encoding a cytochrome P450. Although both interventions increased DDT resistance, neither increased lifespan. Furthermore, dietary restriction increased lifespan without increasing xenobiotic resistance, confirming that the two traits can be uncoupled. Reduced activity of the insulin/Igf signaling (IIS) pathway increases resistance to xenobiotics and extends lifespan in Drosophila, and can also increase longevity in C. elegans, mice, and possibly humans. We identified a nuclear hormone receptor, DHR96, as an essential mediator of the increased xenobiotic resistance of IIS mutant flies. However, the IIS mutants remained long-lived in the absence of DHR96 and the xenobiotic resistance that it conferred. Thus, in Drosophila IIS mutants, increased xenobiotic resistance and enhanced longevity are not causally connected. The frequent co-occurrence of the two traits may instead have evolved because, in nature, lowered IIS can signal the presence of pathogens. It will be important to determine whether enhanced xenobiotic metabolism is also a correlated, rather than a causal, trait in long-lived mice.lifespan | xenobiotic resistance | IIS | nuclear hormone receptor | DHR96

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“…Furthermore, IIS is widely known to control carbohydrate and lipid metabolism across the same range of organisms [16–17,38], and a growing body of literature suggests that alterations in central metabolism are driving forces in the control of inflammatory responses to infection [39–45]. In particular, metabolic shifts may occur to maximally allocate available resources to immunity [39], but may also be due to pathogenic processes stemming from pathogen colonization [40–42]. Accordingly, changes in mosquito metabolism by ILPs produced in the midgut during P. falciparum infection could contribute to their effects on parasite resistance and transmission.…”

Section: Introductionmentioning

confidence: 99%

Two insulin-like peptides differentially regulate malaria parasite infection in the mosquito through effects on intermediary metabolism

Pietri

Pakpour

Napoli

et al. 2016

Biochemical Journal

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Insulin-like peptides (ILPs) play important roles in growth and metabolic homeostasis, but have also emerged as key regulators of stress responses and immunity in a variety of vertebrates and invertebrates. Furthermore, a growing literature suggests that insulin signaling-dependent metabolic provisioning can influence host responses to infection and affect infection outcomes. In line with these studies, we previously showed that knockdown of either of two closely related, infection-induced ILPs, ILP3 and ILP4, in the mosquito Anopheles stephensi decreased infection with the human malaria parasite Plasmodium falciparum through kinetically distinct effects on parasite death. However, the precise mechanisms by which ILP3 and ILP4 control the response to infection remained unknown. To address this knowledge gap, we used a complementary approach of direct ILP supplementation into the blood meal to further define ILP-specific effects on mosquito biology and parasite infection. Notably, we observed that feeding resulted in differential effects of ILP3 and ILP4 on blood-feeding behavior and P. falciparum development. These effects depended on ILP-specific regulation of intermediary metabolism in the mosquito midgut, suggesting a major contribution of ILP-dependent metabolic shifts to the regulation of infection resistance and parasite transmission. Accordingly, our data implicate endogenous ILP signaling in balancing intermediary metabolism for the host response to infection, affirming this emerging tenet in host–pathogen interactions with novel insights from a system of significant public health importance.

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The Acetate Switch of an Intestinal Pathogen Disrupts Host Insulin Signaling and Lipid Metabolism

Cited by 94 publications

References 44 publications

The Drosophila transcriptional network is structured by microbiota

The Drosophila transcriptional network is structured by microbiota

Nuclear hormone receptor DHR96 mediates the resistance to xenobiotics but not the increased lifespan of insulin-mutant Drosophila

Two insulin-like peptides differentially regulate malaria parasite infection in the mosquito through effects on intermediary metabolism

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