Dataset Information

Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans.

ABSTRACT: Fluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variable between patients. We queried whether gut microbes, a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin B6, B9, and ribonucleotide metabolism. Also, disturbances in bacterial deoxynucleotide pools amplify 5-FU-induced autophagy and cell death in host cells, an effect regulated by the nucleoside diphosphate kinase ndk-1. Our data suggest a two-way bacterial mediation of fluoropyrimidine effects on host metabolism, which contributes to drug efficacy. These findings highlight the potential therapeutic power of manipulating intestinal microbiota to ensure host metabolic health and treat disease.

SUBMITTER: Scott TA

PROVIDER: S-EPMC5406385 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans.

Scott Timothy A TA Quintaneiro Leonor M LM Norvaisas Povilas P Lui Prudence P PP Wilson Matthew P MP Leung Kit-Yi KY Herrera-Dominguez Lucia L Sudiwala Sonia S Pessia Alberto A Clayton Peter T PT Bryson Kevin K Velagapudi Vidya V Mills Philippa B PB Typas Athanasios A Greene Nicholas D E NDE Cabreiro Filipe F

Cell 20170401 3

Fluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variable between patients. We queried whether gut microbes, a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effect ...[more]

PMID: 28431245

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Project description:Emerging evidence from both clinical studies and animal models indicates the importance of the interaction between the gut microbiome and the brain in the pathogenesis of neurodegenerative diseases (NDs). Although how microbes modulate neurodegeneration is still mostly unclear, recent studies have started to probe into the mechanisms for the communication between microbes and hosts in NDs. In this review, we highlight the advantages of using Caenorhabditis elegans (C. elegans) to disentangle the microbe-host interaction that regulates neurodegeneration. We summarize the microbial pro- and anti-neurodegenerative factors identified using the C. elegans ND models and the effects of many are confirmed in mouse models. Specifically, we focused on the role of bacterial amyloid proteins, such as curli, in promoting proteotoxicity and neurodegeneration by cross-seeding the aggregation of endogenous ND-related proteins, such as α-synuclein. Targeting bacterial amyloid production may serve as a novel therapeutic strategy for treating NDs, and several compounds, such as epigallocatechin-3-gallate (EGCG), were shown to suppress neurodegeneration at least partly by inhibiting curli production. Because bacterial amyloid fibrils contribute to biofilm formation, inhibition of amyloid production often leads to the disruption of biofilms. Interestingly, from a list of 59 compounds that showed neuroprotective effects in C. elegans and mouse ND models, we found that about half of them are known to inhibit bacterial growth or biofilm formation, suggesting a strong correlation between the neuroprotective and antibiofilm activities. Whether these potential therapeutics indeed protect neurons from proteotoxicity by inhibiting the cross-seeding between bacterial and human amyloid proteins awaits further investigations. Finally, we propose to screen the long list of antibiofilm agents, both FDA-approved drugs and novel compounds, for their neuroprotective effects and develop new pharmaceuticals that target the gut microbiome for the treatment of NDs. To this end, the C. elegans ND models can serve as a platform for fast, high-throughput, and low-cost drug screens that target the microbe-host interaction in NDs.

Project description:Like other intracellular eukaryotic phytopathogens, the devastating rice blast fungus Magnaporthe (Pyricularia) oryzae first infects living host cells by elaborating invasive hyphae (IH) surrounded by a plant-derived membrane. This forms an extended biotrophic interface enclosing an apoplastic compartment into which fungal effectors can be deployed to evade host detection. M. oryzae also forms a focal, plant membrane-rich structure, the biotrophic interfacial complex (BIC), that accumulates cytoplasmic effectors for translocation into host cells. Molecular decision-making processes integrating fungal growth and metabolism in host cells with interface function and dynamics are unknown. Here, we report unanticipated roles for the M. oryzae Target-of-Rapamycin (TOR) nutrient-signaling pathway in mediating plant-fungal biotrophic interface membrane integrity. Through a forward genetics screen for M. oryzae mutant strains resistant to the specific TOR kinase inhibitor rapamycin, we discovered IMP1 encoding a novel vacuolar protein required for membrane trafficking, V-ATPase assembly, organelle acidification and autophagy induction. During infection, ?imp1 deletants developed intracellular IH in the first infected rice cell following cuticle penetration. However, fluorescently labeled effector probes revealed that interface membrane integrity became compromised as biotrophy progressed, abolishing the BIC and releasing apoplastic effectors into host cytoplasm. Growth between rice cells was restricted. TOR-independent autophagy activation in ?imp1 deletants (following infection) remediated interface function and cell-to-cell growth. Autophagy inhibition in wild type (following infection) recapitulated ?imp1. In addition to vacuoles, Imp1GFP localized to IH membranes in an autophagy-dependent manner. Collectively, our results suggest TOR-Imp1-autophagy branch signaling mediates membrane homeostasis to prevent catastrophic erosion of the biotrophic interface, thus facilitating fungal growth in living rice cells. The significance of this work lays in elaborating a novel molecular mechanism of infection stressing the dominance of fungal metabolism and metabolic control in sustaining long-term plant-microbe interactions. This work also has implications for understanding the enigmatic biotrophy to necrotrophy transition.

Project description:Evidence has shown that gut microbiota play a key role in host metabolism and health; however, little is known about the microbial community in the donkey hindgut as well as the interactions that occur between gut microbes and the host. This study aimed to explore the gut microbiome differences by analyzing the microbial community and differentially expressed genes (DEGs) related to lipid metabolism and the immune system along the donkey hindgut. The hindgut tissues (cecum, ventral colon, and dorsal colon) were separated, and the contents of each section were collected from six male donkeys for multi-omics analysis. There were significant differences in terms of dominant bacteria among the three sections, especially between the cecum and dorsal colon sites. For instance, species belonging to Prevotella and Treponema were most abundant in the cecum, while the Clostridiales_bacterium, Streptococcus_equinus, Ruminococcaceae_bacterium, etc., were more abundant in the dorsal colon. Apart from propionate, the concentrations of acetate, isobutyrate, valerate and isovalerate were all lower in the cecum than in the dorsal colon (p < 0.05). Furthermore, we identified some interesting DEGs related to lipid metabolism (e.g., ME1, MBOAT1, ACOX1, ACOX2 and LIPH) and the immune system (e.g., MUC3B, mucin-2-like, IL17RC, IL1R2, IL33, C1QA, and MMP9) between the cecum and dorsal colon and found that the PPAR pathway was mainly enriched in the cecum. Finally, we found a complex relationship between the gut microbiome and gene expression, especially with respect to the immune system, and combined with protein-protein interaction (PPI) data, suggesting that the PPAR pathway might be responsible, at least in part, for the role of the hindgut microbiota in the donkeys' gut homeostasis. Our data provide an in-depth understanding of the interaction between the microbiota and function in the healthy equine hindgut and may also provide guidance for improving animal performance metrics (such as product quality) and equine welfare.

Dataset Information

Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans.

Publications

Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans.

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