Integrative Physiology: At the Crossroads of Nutrition, Microbiota, Animal Physiology, and Human Health

Leulier, François; MacNeil, Lesley T.; Lee, Won jae; Rawls, John F.; Cani, Patrice D.; Schwarzer, Martin; Zhao, Liping; Simpson, Stephen J.

doi:10.1016/j.cmet.2017.02.001

Cited by 104 publications

(86 citation statements)

References 133 publications

(156 reference statements)

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“…These conditions involve dysregulation of metabolism and share evolutionarily conserved genetic and environmental determinants (Leulier et al, 2017). Fruit flies and humans have common molecular regulators of key metabolic pathways, including hormones, transcriptional factors, and signaling molecules that govern cellular and organ metabolism.…”

Section: Introductionmentioning

confidence: 99%

Insulin-Like Peptides Regulate Feeding Preference and Metabolism in Drosophila

et al. 2018

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Fruit flies have eight identified Drosophila insulin-like peptides (DILPs) that are involved in the regulation of carbohydrate concentrations in hemolymph as well as in accumulation of storage metabolites. In the present study, we investigated diet-dependent roles of DILPs encoded by the genes dilp1–5, and dilp7 in the regulation of insect appetite, food choice, accumulation of triglycerides, glycogen, glucose, and trehalose in fruit fly bodies and carbohydrates in hemolymph. We have found that the wild type and the mutant lines demonstrate compensatory feeding for carbohydrates. However, mutants on dilp2,3, dilp3, dilp5, and dilp7 showed higher consumption of proteins on high yeast diets. To evaluate metabolic differences between studied lines on different diets we applied response surface methodology. High nutrient diets led to a moderate increase in concentration of glucose in hemolymph of the wild type flies. Mutations on dilp genes changed this pattern. We have revealed that the dilp2 mutation led to a drop in glycogen levels independently on diet, lack of dilp3 led to dramatic increase in circulating trehalose and glycogen levels, especially at low protein consumption. Lack of dilp5 led to decreased levels of glycogen and triglycerides on all diets, whereas knockout on dilp7 caused increase in glycogen levels and simultaneous decrease in triglyceride levels at low protein consumption. Fruit fly appetite was influenced by dilp3 and dilp7 genes. Our data contribute to the understanding of Drosophila as a model for further studies of metabolic diseases and may serve as a guide for uncovering the evolution of metabolic regulatory pathways.

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Section: Introductionmentioning

confidence: 99%

Insulin-Like Peptides Regulate Feeding Preference and Metabolism in Drosophila

et al. 2018

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“…Recently, Leulier and colleagues defined the “nutrient-microbiota-host axis” to incorporate all of these determinants into a single conceptual framework (Leulier et al, 2017). Our results leverage this idea to connect diverse phenomena into an articulated whole.…”

Section: Discussionmentioning

confidence: 99%

Interplay between mitochondria and diet mediates pathogen and stress resistance inC. elegans

Revtovich

Lee

Kirienko

2017

Preprint

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SummaryDiet is a crucial determinant of organismal biology. Here we demonstrate the dramatic impact of a subtle shift in diet on the ability of Caenorhabditis elegans to survive pathogenic or abiotic stress. Interestingly, this shift occurs independently of canonical host defense pathways, arising instead from improvements in mitochondrial health. Using a variety of assays, we reveal that the most common C. elegans food source (E. coli OP50) results in a vitamin B12 deficiency that compromises mitochondrial homeostasis. Increasing B12 supply by feeding on E. coli HT115 or by supplementing bacterial media with methylcobalamin restored mitochondrial function, even if the bacteria were dead. B12 supplementation also efficiently increased host health without adversely affecting lifespan. Our study forges a molecular link between a dietary deficiency (nutrition/microbiota) and a physiological consequence (host sensitivity), using the host-microbiota-diet framework. The ubiquity of B12 deficiency (~10-40% of US adults) highlights the importance of our findings.

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“…Major population studies have revealed that the microbiome is remarkably stable in healthy adults [23] and vastly rich in metabolic functions [24,25]. It contains 100x more genes than the human genome, with 50% of its content not fully annotated and likely to contribute greatly to the extended metabolic capacity of the holobiont [11,12]. Each persons' microbiome is unique and exhibits wide inter-personal and intra-personal variation, with distinct bacterial communities inhabiting different anatomical regions [21].…”

Section: Targeting the Structure Of The Microbiome For Healthmentioning

confidence: 99%

“…The full scope of these interactions may only be understood using holistic approaches, thus requiring a shift in our understanding of the human body. Together with their microbiota, animals form the holobiont [10] -a single physiological entity with a combined metagenome, and metabolism that is shaped by its environment [11,12] (Figure 1a). Therefore, redefining the holobiont as a target of drug therapy rather than the host only, may also call for a re-evaluation of what therapy is, to include compounds that directly or indirectly affect drug efficacy through an indirect impact on the microbiota.The holobiont exists in a constant flux of dietary metabolites and drugs, which are taken from the environment and circulated between the host and its microbes.…”

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confidence: 99%

Pharmacology in the age of the holobiont

Norvaišas

Cabreiro

2018

Current Opinion in Systems Biology

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Highlights Pharmacomicrobiomics -new frontier in pharmacology  Holobiont -the physiological unit of host and microbes as a drug target  Drugs and drug targets are re-defined in the context of the holobiont  New holistic approach in drug research using holobiont animal models  Exciting new prospects for microbiota-based personalised medicine Glossary:Holobiont -Supra-organism of host and its microbes.Pharmacogenomics -Field of research which combines pharmacology and genomics to study how the genetic make-up of an individual modulates its response to therapeutic drugs [1].Pharmacometabolomics -Field of research which combines pharmacology and metabolomics to study how the metabolome shaped by environment and genetics influence the response of an individual to therapeutic drugs [2].Xenobiotics -An exogenously produced chemical compound found inside an organism. This broad term encompasses therapeutic drugs and dietary metabolites. AbstractDespite the widely acknowledged fact that the microbiota regulates many aspects of human health, the dynamics and factors that govern these interactions remain mostly unknown. Pharmacomicrobiomics is a new research frontier in pharmacology that studies the interaction between drugs and the microbiota. This discipline, by including the microbiota as a key regulator of host health, calls for a redefinition of what constitutes a drug target and ultimately what is a drug or drug therapy. This is supported by recent evidence showing that host physiology can no longer be studied in separation from its microbial ecology and the environmental factors that shape it, as the combination of these elements forms the physiological unit of study -the holobiont. Here we discuss both the novel challenges and untapped opportunities that this new framework creates. On one hand, a more complete understanding of the physiology of the host imposes the development/adaptation of new animal models to address these interactions. In particular, we focus on the advantages and disadvantages of C. elegans as a host organism. On the other hand -a complete understanding of the effects of the microbiota and xenobiotics (e.g. drugs and dietary metabolites) on host health opens new prospects for personalized therapy. Pharmacology has come a long way since the inception of "magic bullet" drugs at the beginning of the 20th century. Intelligent drug design still holds the promise of devising new compounds that specifically affect a disease target yet are harmless to the functioning of the entire organism. The lack of success in achieving such gold standards, associated with high failure of new drugs in clinical trials has led to an increasing interest for drug repurposing [3,4]. Developments in molecular and cellular biology have revealed a number of new drug targets and factors that may affect efficacy and/or side-effects. As a consequence, new branches of pharmacology emerged, like pharmacogenomics and pharmacometabolomics, which aim at understanding how the genetics and the metabolism of an individual can modu...

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Integrative Physiology: At the Crossroads of Nutrition, Microbiota, Animal Physiology, and Human Health

Cited by 104 publications

References 133 publications

Insulin-Like Peptides Regulate Feeding Preference and Metabolism in Drosophila

Insulin-Like Peptides Regulate Feeding Preference and Metabolism in Drosophila

Interplay between mitochondria and diet mediates pathogen and stress resistance inC. elegans

Pharmacology in the age of the holobiont

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