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

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 B-6, B-9, 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.Peer reviewe

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

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

Host-microbe-drug-nutrient screen identifies bacterial effectors of metformin therapy

Metformin is the first-line therapy for treating type-2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, impact the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signalling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modelling of the microbiota in metformin-treated type-2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapie

Detecting changes in the caenorhabditis elegans intestinal environment using an engineered bacterial biosensor.

Caenorhabditis elegans has become a key model organism within biology. In particular, the transparent gut, rapid growing time, and ability to create a defined gut microbiota make it an ideal candidate organism for understanding and engineering the host microbiota. Here we present the development of an experimental model that can be used to characterize whole-cell bacterial biosensors in vivo. A dual-plasmid sensor system responding to isopropyl β-d-1-thiogalactopyranoside was developed and fully characterized in vitro. Subsequently, we show that the sensor was capable of detecting and reporting on changes in the intestinal environment of C. elegans after introducing an exogenous inducer into the environment. The protocols presented here may be used to aid the rational design of engineered bacterial circuits, primarily for diagnostic applications. In addition, the model system may serve to reduce the use of current animal models and aid in the exploration of complex questions within general nematode and host-microbe biology

Sub-lethal toxicity of environmentally relevant concentrations of esfenvalerate to Chironomus ripanus

Integrative studies focused on sub-organismal responses to pyrethroid exposure are important to understand life history responses. In this study, the ecotoxicological effects of esfenvalerate (ESF) on Chironomus riparius were assessed using five biochemical biomarkers related to neurophysiological function (acetylcholinesterase) and oxidative stress (catalase; glutathione-S-transferase; total glutathione and lipid peroxidation). In addition, effects on cellular energy allocation were assessed and all results were compared with organismal level responses (larval growth, emergence and sex ratio). Exposure to sublethal concentrations of ESF caused the failure of C. riparius antioxidant defenses (inhibition of catalase activity and decreased levels of total glutathione), which was reflected as oxidative damage. C. riparius energy budget was decreased by exposure to ESF due to an increased energy consumption. Life cycle tests showed that exposure to ESF impaired C. riparius developmental rates and increased male: female ratios, thereby confirming its toxicity and potential population level effects at environmentally relevant concentrations

Discursos e práticas referentes ao processo de participação comunitária nas ações de educação em saúde: as ações de mobilização comunitária do PCDEN/PE Discourses and practices concerning the social participation process in health education activities: community mobilization in the PCDEN/PE

Neste artigo analisam-se alguns conceitos de participação comunitária nos processos de educação em saúde, contextualizando-os com as experiências práticas em relação às ações dirigidas para a esquistossomose dentro do Programa de Controle das Doenças Endêmicas do Nordeste (Ministério da Saúde do Brasil (MS)/Banco Mundial, 1987). Partindo-se de uma metodologia qualitativa, houve tanto a análise de discursos institucionais (Sucam, FNS e Ministério da Saúde), quanto um trabalho de campo (entrevistas com agentes de saúde e população) realizado na Zona da Mata de Pernambuco (historicamente endêmica) e, principalmente, no Município de Amaraji. Comparando-se discursos e práticas educativas, foram encontrados fatores responsáveis pelas respectivas convergências e divergências, assim como elementos vinculados ao processo social e histórico das populações envolvidas que limitam a eficácia das ações educativas, inclusive de uma maneira mais sistemática.<br>This study analyzes and compares several social participation concepts in health education processes to practical experiences with schistosomiasis prevention measures under the Northeast Endemic Disease Control Program (Brazilian Ministry of Health/World Bank, 1987). Using qualitative methods, institutional documents and discourses were interpreted (Sucam, FNS, and Ministry of Health). A field study was also performed (using interviews with community-based health agents and the general population) in the Zona da Mata region of Pernambuco (a historically endemic area for schistosomiasis), focused in the county of Amaraji. Comparing discourses and educational practices, we found factors that explain respective points of convergence and divergence, as well as elements linked to the social and historical process of the target population which systematically limit the efficacy of such educational measures